WO2016100897A1 - Composés dérivés de l'acide thiadiazolyl-oxyminoacétique - Google Patents

Composés dérivés de l'acide thiadiazolyl-oxyminoacétique Download PDF

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WO2016100897A1
WO2016100897A1 PCT/US2015/066839 US2015066839W WO2016100897A1 WO 2016100897 A1 WO2016100897 A1 WO 2016100897A1 US 2015066839 W US2015066839 W US 2015066839W WO 2016100897 A1 WO2016100897 A1 WO 2016100897A1
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compound
int
sample
solution
standard
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Kristos Adrian Moshos
Valdas Jurkauskas
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Merck Sharp & Dohme Corp.
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Priority to US15/536,545 priority Critical patent/US10059680B2/en
Publication of WO2016100897A1 publication Critical patent/WO2016100897A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles

Definitions

  • This disclosure relates to the synthesis of chemical compounds, including intermediates such as thiadiazolyl-oximinoacetic acid derivatives useful in the manufacture of cephalosporins such as ceftolozane.
  • Ceftolozane is a cephalosporin antibacterial agent of the beta-lactam class ( ⁇ -lactams), also referred to as CXA-101 , FR264205, or by chemical names such as (6R,7R)-5-thia-l - azabicyclo[4.2.0]oct-2-ene-carboxylic acid, 3-[[4-[[[(2-aminoethyl)amino]carbamoyl]amino]-2,3- dihydro-3 mino-2-methyl-l H-pyrazol-l-yl]methyl]-7-[[(2Z)-2-(5-amino-l,2,4-thiadiazol-3-yl)-2-[(l - carboxy-l-methylethoxy)imino]acetyl]amino]-8-oxo; or (6R,7R)-3-[(5-amino-4- ⁇ [(2- aminoethyl)carb
  • Ceftolozane sulfate is also referred to as: 1 H-Pyrazolium, 5-amino-4-[[[(2- aminoethyl)amino]carbonyl]amino]-2-[[(6R,7R)-7-[[(2Z)-2-(5-amino-l,2,4-thiadiazol-3-yl)-2-[(l- carboxy-l-methylethoxy)imino]acetyl]amino]-2-carboxy-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-en-3- yl]methyl]-l -methyl-, sulfate (1 : 1 ); or 7 -[(Z)-2-(5-amino-l ,2,4-thiadiazol-3-yl)-2-(l-carboxy-l - methylethoxyimino)acetamido]-3- ⁇ 3-amino
  • Ceftolozane can be obtained as disclosed in US patent 7, 129,232 and in Toda et al, "Synthesis and SAR of novel parenteral anti- pseudomonal cephalosporins: Discovery of FR264205," Bioorganic & Medicinal Chemistry Letters, 18, 4849-4852 (2008), incorporated herein by reference.
  • the antibacterial activity of ceftolozane is believed to result from its interaction with penicillin binding proteins (PBPs) to inhibit the biosynthesis of the bacterial cell wall which acts to stop bacterial replication.
  • PBPs penicillin binding proteins
  • ceftolozane can be performed via activation of the thiadiazolyl-oximinoacetic acid derivative (I) with methanesulfonyl chloride and .2CO3 in DMA at 10 "C, followed by coupling with the 7-aminocephem (II) by means of Et3N in cold EtOAc/I-bO, affords amide (III).
  • Compound (1) (TATD) is commercially available (CAS No. 76028-96-1). It has now been discovered that the thiadiazolyl-oximinoacetic acid derivative compound (I) (TATD) can be prepared from dimethyl malonate (SM 1, CAS No. 108-59-8) according to methods described herein, e.g., the method depicted in Scheme 1 A or Scheme 2 (the methods of the invention). The methods provide product having desirable purity.
  • a crystal form of compound (I) characterized by an X-ray powder diffraction (XRPD) pattern having peaks at angles (2 theta ⁇ 0.2) of 7.5, 7.9, 1 1.5, 15.7, 17.3, and 23.2.
  • XRPD X-ray powder diffraction
  • Compounds useful in the synthesis of a compound of formula (Z-I), e.g., compound (I), include: (1 ) the compound identified as Int C in Scheme 2, and (2) the compound identified as Int E in Scheme 2.
  • Processes useful in the synthesis of compound (I) include: (3) the formation of the compound Int C from the compound identified as Int B, and (4) the formation of the compound Int E from the compound Int B (e.g., including processes that increase the stability of a compound identified as Int E l in Scheme 2 in situ during conversion of Int D to Int E).
  • Compound Int C is a mono-ester, mono-amide compound resulting from the selective amidation of one ester moiety of the diester compound Int B.
  • the selectivity of the amidation is critical to obtaining high yields of a single oxime stereoisomer.
  • compound Int C is prepared with unexpectedly high selectivity by using a reaction temperature of ⁇ 0 °C, and using conditions comprising ammonium hydroxide (e.g.,
  • Compound Int C can be converted to compound Int D by dehydration of the primary amide of Int C via processes that include reaction with phosphorous pentachloride and pyridine.
  • Compound Int D is converted to the imidate compound Int El and then to the amidine compounds Int El and Int E.
  • Steps in the conversion of Int D to Int E can include: (1) conversion of Int D to Int El using conditions comprising sodium methoxide and methanol; (2) conversion of Int El to Int E2 using conditions comprising acetic acid and ammonium chloride; and (3) conversion of Int E2 to Int E using conditions comprising sodium hydroxide and hydrochloric acid.
  • Int C, Int D, and Int E as well as the processes employing one or more of these compounds are useful, for example, in the manufacture of the compound of formula Z-I, e.g., compound (I) (TATD).
  • Int E can be converted to compound (I) by processes that include the use of and H4SCN (e.g., as described herein).
  • Figure 1 shows a synthetic scheme to prepare compound (VI) (ceftolozane sulfate).
  • Figure 2 shows a synthetic scheme to prepare intermediate compound (IV).
  • Figure 3 shows an HPLC trace for compound Int A.
  • Figure 4 shows an HPLC trace for compound Int B.
  • Figure 5 shows an HPLC trace for compound Int C.
  • Figure 6 shows an HPLC trace for compound Int D.
  • Figure 7 shows an HPLC trace for compound Int E.
  • Figure 8 shows an HPLC trace for compound (I) (TATD).
  • Figure 9 shows a ⁇ -NMR spectrum of Int C.
  • Figure 10 shows a 'H-NMR spectrum of Int D.
  • Figure 11 shows a ⁇ -NMR spectrum of Int E.
  • Figure 12 shows an X-ray powder diffraction (XRPD) pattern for compound (I).
  • Figures 13A and 13B show a listing of peaks for the XRPD pattern of compound (I).
  • GC gas chromatography
  • FID flame ionization detector
  • HPLC high performance liquid chromatography
  • PDA photodiode array
  • RSD relative standard deviation
  • ACN acetonitrile
  • TFA trifluoroacetic acid.
  • C x . y alkyl refers to unsubstituted saturated hydrocarbon groups, including straight- chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain.
  • G-6 alkyl is an alkyl group having two to six carbons.
  • a "linear C x . y alkyl” refers to the "n” form of the alkyl group, for example, a “linear C6 alkyl” is n-hexyl.
  • hydroxyalkyl refers to an alkyl group having one or more, e.g., one, two, or three, hydroxy (i.e., -OH) substituents.
  • a "protecting group” is a moiety that masks the chemical reactivity of a functional group during one or more reactions.
  • a nitrogen protecting group such as tert-butoxycarbonyl (i.e., tert-butyloxycarbonyl, Boc, or BOC) can be introduced at one step to mask the chemical reactivity of a protected nitrogen during one reaction then removed under acidic conditions to allow the formerly protected nitrogen to undergo reaction, e.g., alkylation.
  • a protecting group can be any one known in the art, such as those described in Wuts, P. G. .; Greene, T. W. Greene's Protective Groups in Organic Synthesis, 4 th ed; John Wiley & Sons: Hoboken, New Jersey, 2007, or can be one that is developed in the future.
  • Oxygen and nitrogen protecting groups are known to those of skill in the art.
  • Oxygen protecting groups include, but are not limited to, methyl ethers, substituted methyl ethers (e.g., MOM (methoxymethyl ether), MTM (methylthiomethyl ether), BOM (benzyloxymethyl ether), PMBM or MPM (p-methoxybenzyloxymethyl ether), to name a few), substituted ethyl ethers, substituted benzyl ethers, silyl ethers (e.g., TMS (trimethylsilyl ether), TES (triethylsilylether), TIPS (triisopropylsilyl ether), TBDMS (t-butyldimethylsilyl ether), tribenzyl silyl ether, TBDPS (t-butyldiphenyl silyl ether), to name a few), esters (e.g., formate, acetate, benzoate (Bz
  • Nitrogen protecting groups include, but are not limited to, carbamates (including methyl, ethyl and substituted ethyl carbamates (e.g., Troc), to name a few), amides, cyclic imide derivatives, N-alkyl and N-aryl amines, benzyl amines, substituted benzyl amines, trityl amines, imine derivatives, and enamine derivatives, for example.
  • the oxygen protecting group is a base-labile protecting group (i.e., one that can be removed under basic conditions), such as a methyl group when used as an ester to protect a carboxylic acid.
  • the oxygen protecting group is an acid-labile oxygen protecting group (i.e., one that can be removed under acid conditions), such as tert-butyl, 4- methoxybenzyl, or triphenylmethyl.
  • the oxygen protecting group is an oxidation-reduction sensitive oxygen protecting group, such as a benzyl ether which is removed under catalytic hydrogenation conditions.
  • the oxygen protecting group is a silyl ether, such as TBDMS, TIPS, or TES, which is removed with nucleophilic fluoride.
  • the nitrogen protecting group is a base-labile nitrogen protecting group (i.e., one that is removed under basic conditions), such as 9-fluorenylmethyl carbamate (Fmoc).
  • the nitrogen protecting group is an acid-labile nitrogen protecting group (i.e., one that is removed under acid conditions), such as triphenylmethyl, tert-butyl, tert-butoxycarbonyl, 2-trimethylsilylethoxycarbonyl (Teoc), or 4-methoxybenzyloxycarbonyl.
  • the nitrogen protecting group is an oxidation-reduction sensitive nitrogen protecting group, such as a benzyl, which can be removed under catalytic hydrogenation conditions.
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by the general formulae:
  • R°, R d , and R e each independently represent a hydrogen, an alkyl, an alkenyl, -(CH2) m -R', or R c and R d taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure;
  • R f represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocyclyl or a polycyclyl; and m is zero or an integer from 1 to 8.
  • only one of R c and R d is a carbonyl, e.g., R c , R d , and the nitrogen together do not form an imide.
  • R c and R d each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH2) m -R f .
  • the amino group is basic, meaning the protonated form has a p a > 7.00.
  • an "organic base” is an organic compound comprising at least one basic amino group.
  • the organic base may comprise an alkyl amine, such as triethylamine, diethylamine, and/or diisopropylethylamine, and/or a cyclic amine, such as morpholine, piperidine, piperazine, pyrrolidine, cyclobutylamine, and/or cycloheptylamine.
  • an alcohol includes an organic compound that is or comprises a hydroxyalkyl group.
  • Exemplary alcohols include methanol, ethanol, isopropanol, n-propanol, n-butanol, sec- butanol, tert-butanol, and n-pentanol.
  • an alcohol can comprise, consist essentially of, or consist of methanol.
  • Compound (I) is also known as 'TATD" and "(Z)-2-(5-amino-l ,2,4-thiadiazol-3-yl)-2-(((l - (tert-butoxy)-2-methyl-l-oxopropan-2-yl)oxy)imino)acetic acid” and has the structure shown below.
  • a general sequence to make a compound of formula (Z-I), e.g., compound (I), is shown in Scheme 1A below.
  • a suitable starting material of a compound of formula SM Z-1 is a malonate.
  • R 1 and R 2 are each independently Ci-6 alkyl, preferably C1-3 alkyl, for example, Me, Et, or iPr.
  • R 1 and R can be the same or different.
  • the compound of formula SM Z-1 is converted into an isonitrosomalonate of formula Int Z- A by contacting the compound of formula SM Z-1 with an NO source.
  • an NO source such as that described in Organic Syntheses 1960, 40, 21, which describes using sodium nitrite in aqueous acetic acid as an NO source, can be used to afford Int Z-A.
  • the method optionally comprises a general aqueous workup procedure, such as addition of brine solution and extraction with an ethereal solvent, such as diethyl ether or methyl tert-butyl ether
  • the compound of formula SM Z-1 has the structure of compound SM 1 as described herein.
  • the compound of formula Int Z-A has the structure of compound Int
  • the compound of formula Int Z-A is admixed with a compound of formula Int Z-Al and, optionally, an organic base, such as triethylamine or diisopropylethylamine, in an appropriate solvent, such as tetrahydrofuran (THF), dimethylformamide (DMF) or dimethylacetamide (DMA), for alkylation of the nitroso oxygen to afford a compound of formula Int Z-B.
  • an organic base such as triethylamine or diisopropylethylamine
  • an appropriate solvent such as tetrahydrofuran (THF), dimethylformamide (DMF) or dimethylacetamide (DMA), for alkylation of the nitroso oxygen to afford a compound of formula Int Z-B.
  • X is halo, such as CI or Br.
  • R 3 and R 4 are each independently Ci-6 alkyl, preferably C1-3 alkyl, for example, Me, Et, or iPr. R 3 and R 4 can be the same or different. In some embodiments, R 3 is methyl. In some embodiments, R 4 is methyl.
  • R 3 and R 4 taken together is a C3-7 cycloalkyl, such as cyclopentyl or cyclohexyl.
  • P is an oxygen protecting group, preferably an acid-labile oxygen- protecting group, such as tert-butyl.
  • the compound of fonnula Int Z-Al has the structure of compound SM 2 as described below.
  • the compound of fonnula Int Z-B has the structure of compound Int B.
  • the compound of formula Int Z-B can be converted to a compound of formula Int Z-C by any one of appropriate methods to synthesize a primary amide from an ester, such as contacting the compound of formula Int Z-B with ammonia, optionally in the presence of an alcohol R'OH.
  • the compound of formula Int Z-C has the structure of compound Int C.
  • the compound of formula Int Z-C is then dehydrated to a nitrile of formula Int Z-D by any method to dehydrate a primary amide to a nitrile.
  • a number of methods using reagents, such as phosphorus pentachloride in pyridine, phosphorus oxychloride, or oxalyl chloride, are known in the art to be able to dehydrate a primary amide to a nitrile.
  • the compound of formula Int Z-D has the structure of compound Int D.
  • the compound of formula Int Z-D is then contacted with a compound of fonnula MOR 5 in an alcohol R 5 OH to form an imidate of formula Int Z-El .
  • R 5 is Ci-6 alkyl, preferably C 1 -3 alkyl, for example, Me or Et.
  • the compound of fonnula MOR 5 is a metal alkoxide, wherein M is a metal.
  • M is an alkali metal, e.g., lithium, sodium, or potassium.
  • the compound of formula Int Z-El has the structure of compound Int El.
  • the compound of formula Int Z-El is admixed with an ammonia source to give an amidine of formula Int Z-E2, which can then be contacted with a base to saponify an ester.
  • saponification of a compound of formula Int Z-E2 and subsequent workup can occur by contacting with sodium hydroxide followed by hydrochloric acid to afford an acid of formula Int Z-E.
  • the ammonia source can be ammonia (introduced either as a free gas or already dissolved in a liquid solvent, e.g., methanol) or an ammonium salt, such as ammonium chloride, ammonium bromide, or ammonium acetate.
  • the compound of fonnula Int Z-E2 has the structure of compound Int E2.
  • Scheme IB depicts an alternate sequence to make a compound of formula Int Z-E from a compound of formula Int Z-El .
  • the compound of formula Int Z-El is converted to a compound of formula Int Z-E by first saponification (e.g., by admixing the compound of formula Z-El with a base, such as an aqueous base, for example, a sodium hydroxide solution) to provide a compound of formula Int Z-E3, and then contacting the admixture with an ammonia source.
  • a base such as an aqueous base, for example, a sodium hydroxide solution
  • the conversion of the compound of formula Int Z-E l to a compound of formula Int Z-E comprises any combination of the aforementioned processes (e.g., partial conversion of the compound of fonnula Int Z-El by saponification and then admixing with ammonia as shown in Scheme IB, then a sequence comprising admixing ammonia followed by saponification as shown in Scheme 1 A to effect complete conversion).
  • the compound of formula Int Z-E has the structure of compound Int E.
  • an oxidant such as chlorine, bromine, or iodine
  • a thiocyanate salt e.g., ammonium thiocyanate, sodium thiocyanate, or potassium thiocyanate
  • organic base such as triethylamine
  • the compound of formula (Z-I) has the structure of compound (I).
  • the method of making compound (I) (TATD) comprises the steps shown in Scheme 2. [0065] Scheme 2
  • the process parameters for the preparation of compound Int A are as listed in Table 1. [0069] Table 1 : Process parameters for the preparation of Int A
  • the process parameters for the isolation of compound Int A are as listed in Table 2.
  • Table 2 Process parameters for the quench and workup of Int A
  • the process parameters for the isolation of compound Int B are as listed in Table 4.
  • the process parameters for the preparation of compound Int C are as listed in Table 5.
  • the process parameters for the isolation of compound Int C are as listed in Table 6.
  • the process parameters for the preparation of compound Int D are as listed in Table 8.
  • the process parameters for the isolation of compound Int D are as listed in Table 9.
  • w/w % percentage by equivalent weight ratio (i.e., kg agent per kg Int D * 100)
  • Table 10 describes certain analytical data measured during the preparation of compound Int D from compound Int C according to the synthetic scheme detailed in Scheme 2 above. [0088] Table 10: List of in-process controls for Int D
  • the process parameters for the preparation of compound Int D are as listed in Table 1 1.
  • w/w % percentage by equivalent weight ratio (i.e., kg agent per kg Int E * 100)
  • Table 13 describes certain analytical data measured during the preparation of compound Int E from compound Int D according to the synthetic scheme detailed in Scheme 2 above.
  • Compound (I) (TATD) has the following structural formula:
  • the process parameters for the preparation of compound (I) are as listed in Table 14B.
  • the process parameters for the isolation of compound (I) are as listed in Table 15 A. [0104] Table 15 A: Exemplary process parameters for the isolation of compound (1) (TATD)
  • w/w % percentage by equivalent weight ratio (i.e., kg agent per kg compound (I) x 100)
  • the process parameters for the isolation of compound (I) are as listed in Table 15B. [0106J Table 15B: Exemplary process parameters for the isolation of compound (I) (TATD)
  • the compound Int C is also provided is a method of making compound Int C comprising the step of converting compound Int B into compound Int C.
  • the step of converting compound Int B into compound Int C comprises contacting, e.g., admixing or combining, Int B with N3 ⁇ 4. In another embodiment, it comprises the step of contacting, e.g., admixing or combining, Int B with N3 ⁇ 4, 3 ⁇ 40 and CH3OH.
  • compound Int B is produced by a method comprising the steps of: (a) converting compound SM 1 into compound Int A, and (b) converting compound Int A into compound Int B.
  • compound Int C is converted into compound (I) by a method comprising the steps of: (a) converting compound Int C into compound Int D, (b) converting compound Int D into compound Int El , (c) converting compound Int El into compound Int E2, (d) converting compound Int E2 into compound Int E, and (e) converting compound Int E into compound (I) ⁇
  • step (a) comprises the steps of: (1) combining compound Int E2 with a solution comprising an hydroxide salt; (2) agitating the combination of step (1); (3) addition of acid; and (d) obtaining compound Int E.
  • step (b) comprises the steps of: (1 ) forming a mixture comprising methanol and compound Int E; (2) adding triethylamine; (3) adding bromine; (4) adding a thiocyanate salt; (5) adjusting the pH of the reaction mixture to 2.5 with an aqueous solution of hydrochloric acid; and (6) obtaining compound (I).
  • compound Int E2 is produced by a method comprising the steps of: (a) converting compound Int D into compound Int El , and (b) converting compound Int El into compound Int E2.
  • step (a) comprises converting compound Int D into compound Int El at a temperature between about 0 °C and 18 °C
  • step (b) comprises converting compound Int E 1 into compound Int E2 at a temperature between about 15 °C and 18 °C.
  • step (a) comprises the step of forming a reaction mixture comprising methanol, sodium methoxide, and compound Int D, thereby forming compound Int El .
  • step (b) comprises the step of adjusting the pH of the reaction mixture to 6.5 with acetic acid and admixing, e.g., adding, ammonium chloride, thereby converting compound Int El into compound Int E2.
  • compound Int D is produced by a method comprising the steps of: (a) converting compound Int B into compound Int C, and (b) converting compound Int C into compound Int D.
  • step (a) comprises the steps of: (1) contacting, e.g., combining, compound Int B with ammonia, water and methanol; (2) adjusting the pH of the reaction mixture to a pH of about 5 with hydrochloric acid; and (3) obtaining compound Int C.
  • step (b) comprises the steps of: ( 1) forming a reaction mixture comprising methyl tert-buty] ether, phosphorus pentachloride and pyridine; (2) combining compound Int C with the reaction mixture of step ( 1); (3) adding an aqueous solution of methanol; and (4) obtaining compound Int D.
  • compound Int B is produced by a method comprising the steps of: (a) converting compound SM 1 into compound Int A, and (b) converting compound Int A into compound Int B.
  • step (a) comprises the steps of: ( 1) forming a reaction mixture comprising water, sodium nitrite, acetic acid and compound SM 1 ; (2) adjusting the pH of the reaction mixture to about 6.5 with acetic acid; and (3) obtaining compound Int A.
  • step (b) comprises the steps of: (1) combining compound Int A with compound SM 2, triethylamine and dimethylformamide; and (2) obtaining compound Int B. 6.4. Crystalline Form of Compound (1)
  • crystal form of compound (I) characterized by an X-ray powder diffraction (XRPD) pattern having peaks at angles (2 theta ⁇ 0.2) of 7.5, 7.9, 1 1.5, 15.7, 17.3, and 23.2.
  • the crystal form of compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern having further peaks at angles (2 theta ⁇ 0.2) of 14.1, 14.7, 16.2, 19.9, 20.7, 23.5, and 29.9.
  • the crystal form of compound (I) is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at angles (2 theta ⁇ 0.2) of7.5, 7.9, 10.2, 11.5, 15.7, 17.3, 23.2 and 29.9.
  • XRPD X-ray powder diffraction
  • the crystal form of compound (I) is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at angles (2 theta ⁇ 0.2) of 7.5, 7.9, 10.2, 1 1.5, 14.1 ,
  • the crystal form of compound (I) is characterized by an X-ray powder diffraction (XRPD) pattern having one or more, two or more, three or more, four or more, or five or more peaks at angles (2 theta ⁇ 0.2) of 7.5, 7.9, 10.2, 1 1.5, 14.1 , 14.7, 15.1, 15.7, 16.2, 17.3,
  • XRPD X-ray powder diffraction
  • the crystal form of compound (I) is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at the angles (2 theta ⁇ 0.2) listed in the Table of Figure 13.
  • XRPD X-ray powder diffraction
  • the crystal form of compound (I) is characterized by an X-ray powder diffraction (XRPD) pattern substantially corresponding to Figure 12.
  • Compound (I) is a useful intermediate in the production of antibiotics, particularly cettolozane, and salts thereof.
  • Compositions comprising compound (I) and intermediates are provided herein. Also provided are compositions produced or occurring during the methods of making compound (I).
  • compositions comprising compounds SM 1 (dimethyl malonate) and Int A; a composition comprising Int A and Int B; a composition comprising Int B and Int C; a composition comprising SM 1, Int A and Int B; a composition comprising Int A, Int B and Int C; a composition comprising SM 1, Int A, Int B and Int C.
  • composition may be produced during the methods of the invention to prepare intermediate D (Int D): a composition comprising compounds Int C and Int D.
  • compositions comprising compounds Int D and Int El a composition comprising compounds Int E l and Int E2; a composition comprising compounds Int E2 and Int E; a composition comprising compounds Int D, Int El and Int E2; a composition comprising compounds Int El, Int E2 and Int E; and a composition comprising compounds Int D, Int El, Int E2 and Int E.
  • composition may be produced during the methods of the invention to prepare compound (I) (TATD): a composition comprising compounds Int E and compound (I).
  • Holding tank 1 was charged with J3 ⁇ 40 (300 kg, 1.50 vol) and NaN0 2 ( 161.3 kg, 1.54 equiv), and agitated for 30 minutes at a temperature between 20 and 25 °C.
  • Reactor 1 was charged with acetic acid (202.3 kg, 2.22 equiv) and the temperature was adjusted to a range between 20 and 30 °C. Then, reactor 1 was charged with SM 1 (200.6 kg, 1.00 eq) at a temperature between 20 and 30 °C. The solution in holding tank 1 was transferred to reactor 1 at a temperature between 20 and 30 °C over the course of 2 to 3 hours. The contents of reactor 1 were agitated for 12 to 13 hours at a temperature between 20 and 30 °C.
  • Reactor 1 was charged with a 25% NaCl solution (214 kg, 0.89 vol), followed by methyl tert- butyl ether (MTBE) (447.6 kg, 3.02 vol), and the batch was agitated for 30 minutes at a temperature between 20 and 30 °C. The agitation was stopped, and the batch was allowed to stand for 30 minutes until the phases separated. The lower aqueous phase was transferred to holding tank 1. The upper organic layer was transferred to holding tank 2. The lower aqueous phase in holding tank 1 was transferred back to reactor 1, and reactor 1 was charged with MTBE (452.0g, 3.05 vol). The contents of reactor 1 were agitated for 60 minutes at a temperature between 20 and 30 °C.
  • MTBE methyl tert- butyl ether
  • reactor 1 was charged with NaHCC (105.4 kg, 0.83 eq) to adjust pH to 6.9, and the batch was agitated for 30 minutes at a temperature between 20 and 30 °C. The agitation was stopped, and the batch was allowed to stand for 30 minutes until the phases separated. The lower aqueous phase was transferred to holding tank 2. A portion of the 25% NaCl solution (205.0 kg, 0.85 vol) was charged to reactor 1 , and the batch was agitated for 30 minutes at a temperature between 20 and 30 °C. The agitation was stopped, and the batch was allowed to stand for 30 minutes until the phases separated. The lower aqueous phase was transferred to holding tank 2.
  • NaHCC 105.4 kg, 0.83 eq
  • Reactor 1 was charged with NEt 3 (295.2 kg, 1.92 eq), followed by SM 2 (350.0 g, 1.03 eq) at a temperature between 20 and 30 °C. Then the batch was adjusted to a temperature between 45 and 50 °C and agitated for 20 to 25 hours, while maintaining this temperature.
  • Reactor 1 was charged with MTBE (308.2 kg. 2.08 vol), and the batch was agitated for 30 minutes. Then the agitation was stopped and the batch was allowed to stand for 30 minutes until the phases separated. The lower aqueous layer was transferred to holding tank 1. The organic layer in holding tank 2 was transferred to reactor 1. Then, reactor 1 was charged with a 25% NaCl (466.0 g, 1.94 vol) solution. The contents of reactor 1 were agitated for 30 minutes. Then the agitation was stopped, and the batch was allowed to stand for 30 minutes until the phases separated. The lower aqueous layer was transferred to holding tank 1. Reactor 1 was charged with a 25% NaCl (449.0 kg, 1.87 vol) solution. The contents of reactor 1 were agitated for 30 minutes.
  • compound Int C can be prepared with unexpectedly high selectivity by selection of the reaction temperature (e.g., at or below about 0 °C) and using conditions comprising ammonium hydroxide (e.g., as disclosed herein).
  • concentration e.g., at or below about 0 °C
  • ammonium hydroxide e.g., as disclosed herein.
  • the batch comprising Int B was transferred to reactor 3. Then reactor 3 was charged with methanol (MeOH, 411.0 kg, 2.60 vol), and the batch was adjusted to a temperature between -5 and -2 °C. A 25% (w/w%) NH 3 /H 2 0 (185.8 kg, 1.02 vol) solution was charged to reactor 3, while maintaining the batch at a temperature between -5 and 5 °C. The batch was agitated for 3 to 6 hours at a temperature between -5 and 5 °C, then the batch was adjust to a temperature between -10 and O °C.
  • Pre-cooled water (790 kg, 3.95 vol) at 0 to 5 °C was transferred to reactor 3, while maintaining the batch temperature at -10 to 5 °C.
  • Pre-cooled 2N HC1 (771 kg, 3.50 vol) at 0 to 5 °C was transferred to reactor 3 to achieve a pH of 5, while maintaining the batch temperature between - 10 and 5 °C.
  • the batch was concentrated ( 1800 to 2200 L, 9.00-11.00 vol) under reduced pressure, while maintaining the batch temperature below 40 °C.
  • the batch was agitated for 1 to 2 hours at a temperature between 15 and 25 °C.
  • Reactor 1 was charged with MTBE (600.0 kg, 2.70 vol) and the temperature was adjusted to a range between -10 and 0 °C. Then reactor 1 was charged with PCI5 (264.7 kg, 1.22 eq).
  • reactor 1 was charged with Int C (300.4 kg, 1.00 eq) via portion-wise addition, while maintaining the batch temperature below 20 °C.
  • the contents of reactor I were agitated for 10 to 18 hours at a temperature between 15 and 20 °C.
  • Reactor 2 was charged with 3 ⁇ 40 (930 kg, 3.10 vol), and the temperature was adjusted to a range between 0 and 3 °C. The contents of reactor 1 were transferred to reactor 2, while maintaining the temperature of reactor 2 below 20 °C. The contents of reactor 2 were agitated for 60 to 90 minutes at a temperature between 10 and 20 °C, or until the pH value was 3. The agitation was stopped, and the batch was allowed to stand for 2 to 3 hours until the phases separated. The lower aqueous layer was transferred to holding tank 1. Reactor 2 was charged with a 25% NaCl (600 kg, 1.67 vol) solution, followed by MeOH (71 kg, 0.30 vol), and the batch was adjusted to a temperature between 20 and 30 °C.
  • the batch was agitated for 30 minutes. Then the agitation was stopped, and the batch was allowed to stand for 45 to 60 minutes until the phases separated.
  • the lower aqueous layer was transferred to holding tank 1.
  • Reactor 2 was charged with a 25% NaCl (572 kg, 1.59 vol) solution, followed by MeOH (36 kg, 0.15 vol), and the batch was adjusted to a temperature between 20 and 30 °C.
  • the batch was agitated for 30 minutes. Then the agitation was stopped, and the batch was allowed to stand for 45 to 60 minutes until the phases separated.
  • the lower aqueous layer was transferred to holding tank 1.
  • the batch (in reactor 2) was charged with active carbon (60 kg).
  • reactor 2 The contents of reactor 2 were adjusted to a temperature between 50 to 55 °C and then were agitated for 30 to 60 minutes at this temperature.
  • the batch temperature is adjusted to 20 to 30 °C then filtered through a pad of diatomite into reactor 3.
  • the batch in reactor 3 was concentrated under reduced pressure to 301 to 452 L (1.0-1.5 vol) while maintaining the temperature below 40 °C.
  • Reactor 3 was charged with MeOH (290.0 kg, 1.22 vol).
  • the batch was concentrated under reduced pressure to 301-452 L, 1.0-1.5 vol), while maintaining the batch temperature below 40 °C.
  • the water content was deemed acceptable when ⁇ 0.2% water remained by Karl Fischer (KF) titration (method: TWI- QC-020.01).
  • the temperature of reaction step 1) above is maintained at a temperature effective to increase the yield of the Int E compound from Int D (including desirably high rates of conversion of Int D to Int El).
  • the compounds Int El and Int E2 can be formed in situ, and Int E is isolated from the reaction mixture at the conclusion of the process described as Step 3 above.
  • MeONa is used in the conversion of Int D to Int El in the reaction scheme above, other embodiments include the use of any suitable alcohol (e.g., ethanol, isopropanol) or suitable salts thereof (e.g., sodium salts) in place of or in addition to the MeONa reagent.
  • the suitable alcohol can be used with any suitable leaving group (e.g., HCI).
  • the temperature of the reaction of Int D is preferably selected to maximize the yield of Int E, including temperatures that maximize the yield for the conversion of Int D to Int El .
  • the temperature for the reaction of Int D is preferably 17 degrees C or lower (e.g., 0 degrees C, or lower), although the reaction(s) can be perfonned at other temperatures (e.g., 0-18 °C).
  • processes include the saponification of Int E substrate (i.e., Int E2).
  • the order of reaction can affect the yield of the product.
  • reactor 1 was charged with a 47 % NaOH (245.0 kg, 0.63 vol) solution slowly, while maintaining the batch at a temperature between 0 and 20 °C. Then the batch was adjusted to a temperature between 15 and 20 °C, and agitated for 2 to 4 hours at this temperature. The batch was adjusted to a temperature between 5 and 10 °C. Then reactor 1 was charged with 3N HCI (675.0 kg, 2.58 vol) via dropwise addition to adjust pH to 7, while maintaining the batch temperature between 5 and 20 °C.
  • 3N HCI 675.0 kg, 2.58 vol
  • the solution yield was unexpectedly high at room temperature, although lower reaction temperatures can increase stability and yields.
  • the intermediate E 1 was found to be unstable at elevated reaction temperatures, as can be seen in Table 17 above.
  • the solution yield and solution assay are constant for up to 25 hours at 0 °C. However if the reaction is performed at 17 °C the solution yield drops from the 1 hour time point of 75.9% to 63.6% at 5 hours. If the reaction is maintained at 30 °C, the solution yield decreases from 59.9% to 37.1 % over the same time period. From this data the reaction should be performed below 10 °C, preferably below 0 °C, although other embodiments include temperatures at or below about 17 °C.
  • Activated charcoal (10.6 kg) was charged to reactor 1 and the temperature was adjusted to a value between 30 and 40 °C. Then the batch was agitated the aforementioned temperature for 30 to 60 minutes. The batch in reactor 1 was charged with diatomite (12.8kg). Then the batch was centrifuged and the filtrate was transferred to reactor 1. The batch was concentrated under reduced pressure to a volume between 555 to 777 L (5-7 vol), while maintaining the temperature below 40 °C. The batch was adjusted to a temperature between 10 and 20 °C. 1 N HC1 (464 kg, 4.2 vol) was charged to reactor 1 to adjust pH to 2.5. The batch was agitated for 30 to 60 minutes at a temperature between 10 and 20 °C.
  • the batch was centrifuged to afford the product as a wet cake, and then the wet cake was transferred to reactor 1.
  • Reactor 1 was charged with THF (972.0 kg, 9.9 vol) followed by H2O (44.6 kg, 0.4 vol).
  • the batch temperature was adjusted to a temperature between 50 and 60 °C and then agitated for 30 to 60 minutes at a temperature between 50 and 60 °C.
  • the batch was adjusted to a temperature between 40 and 50 °C and then was charged with activated charcoal (5.0 kg).
  • the batch was adjusted to a temperature between 50 and 60 °C, and then the batch was agitated for 30 to 60 minutes at this temperature.
  • the batch was filtered, and the filtrate was transferred to reactor 2.
  • reactor 2 The contents of reactor 2 were concentrated to a volume between 222 and 444 L (2-4 vol), while maintaining the temperature below 40 °C. The batch was adjusted to a temperature between 50 and 60 °C, and then reactor 2 was charged with MTBE (318.0 kg, 3.87 vol) via dropwise addition. The batch was cooled to a temperature between 0 and 5 °C, and the batch was agitated for 1 to 2 hours.
  • Compound Int E can be converted to TATD according to the reaction scheme above.
  • the resulting TATD in solution can be precipitated by addition of a strong acid (e.g., HC1).
  • a strong acid e.g., HC1
  • Adding an alcohol and water e.g., MeOH and water
  • the amount of water is selected to maintain solubility temperature less than the degradation of TATD.
  • the speed of cooling can affect the particle size of the solid TATD, with faster cooling resulting in smaller particles.
  • Table 18 details some of the key differences between Method Al and Method A2 at multikilogram scale.
  • Method A2 reduces the number of operations and the amount of waste material generated by the process.
  • the protocol change from Method Al to Method A2 results in a lower amount of by-products.
  • the modification in Method A2 as compared to the corresponding procedure in Method Al leads to shorter reaction time or reactor cleaning time, thus reducing overall cycle time and overall cost.
  • Table 19 details the average molar yield, cycle time, and waste generated (kg waste per kg product [kg/kg]) in a multikilogram synthesis of compound (I) from compound Int C using Method Al or Method A2.
  • Method Al proceeds to desired compound (I) in 31% overall yield; a more preferred Method A2 proceeds in the higher overall yield of 46% overall.
  • Some key characteristics of the Method A2 as compared with Method Al include a higher yield of the conversion from compound Int D to Int E (59% vs. 43% in Method Al), and a higher yield of the conversion from compound Int E to compound (I) (86% vs. 78% in Method Al).
  • Method A2 the waste generated in certain conversions is reduced in Method A2 as compared with the corresponding conversion in Method Al : (1) from Int C to Int D (24 kg/kg vs. 45 kg/kg in Method Al), and (2) from Int D to Int E (20 kg/kg vs. 38 kg/kg in Method Al). Also, incremental improvements in the cycle time for certain conversions in Method A2 compared with the corresponding conversion in Method Al afford a significant reduction in overall cycle time for the process from compound Int C to compound (I) (32 days vs. 40 days in Method Al). [0160] Table 20: Quality testing of batches of compound (I) from Method Al and Method A2
  • Table 20 demonstrates that both Method Al and Method A2 affords high quality batches of compound (I) that meet desired specification criteria. All batches gave off-white to white solid. The water content (by Karl-Fischer (KF) analysis) (target ⁇ 0.5%), assay (target > 98.0%), purity (target > 99.0%), and individual unspecified impurities (target ⁇ 0.20% each) met target criteria in each case. No new impurities were detected in Method A2 compared to Method Al .
  • Table 21 Residual solvent analysis of compound (1) batches
  • Tables 21 and 22 show further analyses of selected batches prepared by Method Al and Method A2.
  • compound (I) showed residual solvent levels below target criteria ( ⁇ 1500 ppm THF, ⁇ 300 ppm methanol, ⁇ 500 ppm MTBE, and ⁇ 200 ppm pyridine) (Table 21).
  • Additional batch analysis demonstrated that each batch also showed low residual levels of impurities such as heavy metals ( ⁇ 20 ppm), salts ( ⁇ 1000 ppm bromide, ⁇ 100 ppm nitrite, and ⁇ 150 ppm thiocyanate), and phosphorus ( ⁇ 10 ppm) (Table 22).
  • each batch showed an acceptable residue on ignition ( ⁇ 0.2%) and a melting point within the accepted range.
  • the hold time at 250 °C can be extended according to the different characteristic of the sample.
  • WSTD represents the weight of C 1 1030405-SM 1 in standard solution (mg)
  • Ws represents the weight of sample (mg)
  • VSTD represents the dilution volume of C I 1030405-SMl in standard solution (mL)
  • Vs represents the dilution volume of sample (mL)
  • ASTD represents the peak area of CI 1030405-SM l in standard solution
  • Pw represents the assay value of CI 1030405-SMl reference standard
  • Mobile Phase A (0.05%TFA -H 2 0): Accurately transfer 0.5 mL TFA into 1000 mL purified water and mix well. The solution should be filtrated and degassed before use.
  • Mobile Phase B (0.05%TFA -ACN): Accurately transfer 0.5 mL TFA into 1000 mL acetonitrile and mix well.
  • WSTD represents the weight of CI 1030405-A in standard solution (mg)
  • Ws represents the weight of sample (mg)
  • VsTD represents the dilution volume of CI 1030405-A in standard solution (mL)
  • Vs represents the dilution volume of sample (mL)
  • a STD represents the peak area of CI 1030405-A in standard solution
  • Pw die assay value of CI 1030405-A reference standard
  • W STD represents the weight of C 1 1030405-A in standard solution (mg)
  • Ws represents the weight of sample (mg)
  • V STD represents the dilution volume of CI 1030405-A in standard solution (mL)
  • Vs represents the dilution volume of sample (mL)
  • a S TD represents the peak area of CI 1030405-A in standard solution
  • Pw represents the assay value of CI 1030405-A reference standard
  • the blank should not contain peaks that may interfere with the quantitation of the relevant solvents. If the signal to noise (S N) of interference peak is >10, the peak area must be revised before it is used to calculate the relevant residual solvent in the sample.
  • S N signal to noise
  • WSTD represents the weight of specified solvent in standard solution (mg)
  • Ws represents the weight of sample (mg)
  • VSTD represents the dilution volume of specified solvent in standard solution (mL)
  • Vs represents the dilution volume of sample (mL)
  • ASTD represents the revised peak area of specified solvent in standard solutions
  • HPLC equipped with PDA detector and auto-sampler
  • Mobile Phase A (0.05% TFA-H 2 0): Accurately transfer 0.5 mL TFA into 1000 mL purified water and mix well. The solution should be filtrated and degassed before use.
  • Mobile Phase B (0.05% TFA-ACN): Accurately transfer 0.5 mL TFA into 1000 mL acetonitnle and mix well.
  • A/B % ⁇ x l00%
  • SA represents the peak area of C 11030405-A in sample solution
  • S B represents the peak area of CI 1030405-B in sample solution
  • W STD represents the weight of CI 1030405-B in standard solution (mg)
  • Ws represents the weight of sample (mg)
  • VSTD represents the dilution volume of CI 1030405-B in standard solution (mL)
  • Vs represents the dilution volume of sample (mL)
  • ASTD represents the peak area of C1 1030405-B in standard solution
  • Pw represents the assay value of CI 1030405-B reference standard
  • Residual Compound B (g/L) WsT » x Pw x A s ⁇ K
  • WSTD represents the weight of C 1 1030405-B in standard solution (mg)
  • s represents the weight of sample (mg)
  • VSTD represents the dilution volume of CI 1030405-B in standard solution (mL)
  • Vs represents the dilution volume of sample (mL)
  • ASTD represents the peak area of C I 1030405-B in standard solution
  • Pw represents the assay value of C I 1030405-B reference standard
  • CI 1030405-B If an interference peak is observed, it should be ⁇ 0.1 % peak area of CI 1030405-B in
  • Wi represents the weight of CI 1030405-B in 1# standard solution (mg)
  • W2 represents the weight of CI 1030405-B in 2# standard solution (mg)
  • A2 represents the peak area of CI 1030405-B in 2# standard solution
  • Ai represents the peak area of C I 1030405-B in 1# standard solution
  • ASTD represents the peak area of C 11030405-B in standard solution
  • VSTD represents the dilution volume of standard solution (mL)
  • WSTD represents the weight of C I 1030405-B in standard solution (mg)
  • Pw represents the assay value of C I 1030405-B reference standard
  • Ws represents the weight of sample (mg)
  • Vs represents the dilution volume of sample (mL)
  • RF represents the average value of RF for two standard solutions
  • HPLC equipped with PDA detector and auto-sampler
  • Mobile Phase A (0.05%TFA -H20): Accurately transfer 0.5 mL TFA into 1000 mL purified water and mix well. The solution should be filtrated and degassed before use.
  • Mobile Phase B (0.05%TFA -ACN): Accurately transfer 0.5 mL TFA into 1000 mL acetonitrile and mix well.
  • S B represents the peak area of CI 1030405-B in sample solution
  • Sc represents the peak area of CI 1030405-C in sample solution
  • W S TD represents the weight of C 11030405-C in standard solution (mg)
  • Ws represents the weight of sample (mg)
  • V S TD represents the dilution volume of C I 1030405-C in standard solution (mL)
  • Vs represents the dilution volume of sample (mL)
  • a STD represents the peak area of CI 1030405-C in standard solution
  • Pw represents the assay value of CI 1030405-C reference standard represents the dilution ratio
  • WSTD represents the weight of C 11030405-C in standard solution (mg)
  • Ws represents the weight of sample (mg)
  • V STD represents the dilution volume of C 11030405-C in standard solution (mL)
  • Vs represents the dilution volume of sample (mL)
  • a S TD represents the peak area of C I 1030405-C in standard solution
  • Pw represents the assay value of CI 1030405-C reference standard represents the dilution ratio
  • sample Accurately weigh approximately 30 mg sample into a 100 mL volumetric flask, dissolve and dilute to the volume with diluent, mix well. The weight of sample may be adjusted to reach equivalent intensity of C I 1030405-C in the sample as it is in the standard. Two sample solutions should be prepared in parallel and labeled as 1# sample solution and 2# sample solution.
  • CI 1030405-C If an interference peak is observed, it should be ⁇ 0.05% peak area of CI 1030405-C in
  • Wi represents the weight of CI 1030405-C in 1 # standard solution (mg)
  • W 2 represents the weight of CI 1030405-C in 2# standard solution (mg)
  • A2 represents the peak area of CI 1030405-C in 2# standard solution
  • Ai represents the peak area of CI 1030405-C in 1# standard solution
  • a STD represents the peak area of CI 1030405-C in standard solution
  • VSTD represents the dilution volume of standard solution (mL)
  • WSTD represents the weight of CI 1030405-C in standard solution (mg)
  • Pw represents the assay value of CI 1030405-C reference standard
  • Ws represents the weight of sample (mg)
  • Vs represents the dilution volume of sample (mL)
  • RF represents the average value of RF for two standard solutions
  • HPLC equipped with PDA detector and auto-sampler
  • Mobile Phase A (0.05%TFA -H20): Accurately transfer 0.5 mL TFA into 1000 mL purified water and mix well. The solution should be filtrated and degassed before use.
  • Sc represents the peak area of C I 1030405-C in sample solution
  • WSTD represents the weight of CI 1030405-D in standard solution (mg)
  • Ws represents the weight of sample (mg)
  • V S TD represents the dilution volume of CI 1030405-D in standard solution (mL)
  • Vs represents the dilution volume of sample (mL)
  • ASTD represents the peak area of CI 1030405-D in standard solution
  • Pw represents the assay value of CI 1030405-D reference standard represents the dilution ratio
  • aqueous phase Inject sample solution directly. If the concentration is too high, dilute to appropriate concentration with diluent 2 to reach equivalent intensity of CI 1030405-D in the sample as it is in the standard.
  • active carbon Accurately weigh approximately 0.5 g sample into a 10 mL volumetric flask, dissolve and dilute to the volume with diluent 1, mix well. Degas and filter using a 0.45 ⁇ filter. The weight of sample may be adjusted to reach equivalent intensity of CI 1030405-D in the sample as it is in the standard.
  • WSTD represents the weight of C 11030405-D in standard solution (mg)
  • Ws represents the weight of sample (mg)
  • V S T D represents the dilution volume of CI 1030405-D in standard solution (mL)
  • Vs represents the dilution volume of sample (mL)
  • a STD represents the peak area of CI 1030405-D in standard solution
  • Pw represents the assay value of CI 1030405-D reference standard represents the dilution ratio
  • sample Accurately weigh approximately 50 mg sample into a 100 mL volumetric flask, dissolve and dilute to the volume with diluent, mix well. The weight of sample may be adjusted to reach equivalent intensity of CI 1030405-D in the sample as it is in the standard. Two sample solutions should be prepared in parallel and labeled as ⁇ # sample solution and 2# sample solution.
  • CI 1030405-D If an interference peak is observed, it should be ⁇ 0.05% peak area of CI 1030405-D in
  • W represents the weight of CI 1030405-D in 1# standard solution (mg)
  • W2 represents the weight of CI 1030405-D in 2# standard solution (mg)
  • A2 represents the peak area of CI 1030405-D in 2# standard solution
  • Ai represents the peak area of CI 1030405-D in 1# standard solution
  • ASTD represents the peak area of CI 1030405-D in standard solution
  • VSTD represents the dilution volume of standard solution (mL)
  • WSTD represents the weight of CI 1030405-D in standard solution (mg)
  • Pw represents the assay value of CI 1030405-D reference standard
  • Ws represents the weight of sample (mg)
  • Vs represents the dilution volume of sample (mL)
  • Mobile Phase A (0.05%TFA -H20): Accurately transfer 1.0 mL TFA into 2000 mL purified water and mix well. The solution should be filtrated and degassed before use.
  • S D represents the peak area of C 1 1030405-D in sample solution
  • S EI represents the peak area of CI 1030405-E 1 in sample solution (the peak should be confirmed by the project leader)
  • SEI represents the peak area of C 11030405-E2 in sample solution (the peak should be confirmed by the project leader)
  • S E represents the peak area of C 1 1030405-E in sample solution
  • W S TD represents the weight of C I 1030405-E in 2#standard solution (mg)
  • Ws represents the weight of sample (mg)
  • VSTD represents the dilution volume of CI 1030405-E in 2# standard solution (mL)
  • Vs represents the dilution volume of sample (mL)
  • ASTD represents the peak area of CI 1030405-E in 2# standard solution
  • Pw represents the assay value of CI 1030405-E reference standard
  • Residual Compound E (%, w/w) W m * p * ⁇ v , * A s ⁇ 1 0QO/o
  • Residual Compound E (mg/g) W s TO * Pw y V s x j QQ Q
  • Residual Compound E (g/g) W -> x Pw v ⁇ x A >
  • WSTD represents the weight of CI 1030405-E in standard solution (mg)
  • Ws represents the weight of sample (mg)
  • VSTD represents the dilution volume of CI 1030405-E in standard solution (mL)
  • Vs represents the dilution volume of sample (mL)
  • ASTD represents the peak area of CI 1030405-E in standard solution
  • Pw represents the assay value of CI 1030405-E reference standard
  • K represents the dilution ratio
  • the blank should not contain peaks that may interfere with the determination of CI 1030405-E. If an interference peak is observed, it should be ⁇ 0.05% peak area of CI 1030405-E in 1# standard solution.
  • W i represents the weight of CI 1030405-E in 1 # standard solution (mg '
  • W2 represents the weight of CI 1 030405-E in 2# standard solution (mg)
  • A2 represents the peak area of C I 1030405-E in 2# standard solution
  • Ai represents the peak area of CI 1030405-E in 1 # standard solution

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Abstract

Des dérivés d'acide thiadiazolyle-oxyminoacétique ont été synthétisés, lesquels sont utiles dans la fabrication de composés antibiotiques à base de céphalosporine. Le composé (1) (TATD) est disponible dans le commerce (N° CAS76028-96-1). Il a maintenant été découvert que le composé (1) dérivé de l'acide thiadiazolyl-oxyminoacétique (TATD) peut être préparé à partir de diméthyl malonate (SM 1, N° CAS108-59-8) selon les procédés décrits. Les procédés permettent d'obtenir des produits qui présentent une pureté souhaitable.
PCT/US2015/066839 2014-12-18 2015-12-18 Composés dérivés de l'acide thiadiazolyl-oxyminoacétique WO2016100897A1 (fr)

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CN108003115A (zh) * 2017-11-28 2018-05-08 浙江东邦药业有限公司 一种ceftolozane侧链的制备方法
US10035774B2 (en) 2014-12-18 2018-07-31 Merck Sharp & Dohme Corp. Pyrazolyl carboxylic acid and pyrazolyl urea derivative compounds
US10059680B2 (en) 2014-12-18 2018-08-28 Merck Sharp & Dohme Corp. Thiadiazolyl-oximinoacetic acid derivative compounds
US10214543B2 (en) 2014-12-30 2019-02-26 Merck Sharp & Dohme Corp. Synthesis of cephalosporin compounds
US10308666B2 (en) 2014-12-23 2019-06-04 Merck Sharp & Dohme Corp. 7-aminocephem derivative compounds

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EP0064582A1 (fr) * 1978-12-29 1982-11-17 Fujisawa Pharmaceutical Co., Ltd. Produits de départ pour la préparation de céphalosporines et leurs procédés de préparation
JPH01135778A (ja) * 1987-11-19 1989-05-29 Fujisawa Pharmaceut Co Ltd 酢酸誘導体の製造法
US20050096306A1 (en) * 2003-09-18 2005-05-05 Fujisawa Pharmaceutical Co. Ltd. Cephem compounds
US20070037786A1 (en) * 2002-10-30 2007-02-15 Wakunaga Pharmaceutical Co., Ltd. Cephem compounds

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KR101719556B1 (ko) * 2011-03-30 2017-03-24 주식회사 레고켐 바이오사이언스 신규한 세파로스포린 유도체 및 이를 함유하는 의약 조성물
US9695196B2 (en) 2014-06-20 2017-07-04 Merck Sharp & Dohme Corp. Reactions of thiadiazolyl-oximinoacetic acid derivative compounds
WO2016025839A1 (fr) 2014-08-15 2016-02-18 Merck Sharp & Dohme Corp. Synthèse de composés de céphalosporine
US10221196B2 (en) 2014-08-15 2019-03-05 Merck Sharp & Dohme Corp. Intermediates in the synthesis of cephalosporin compounds
WO2016100897A1 (fr) 2014-12-18 2016-06-23 Merck Sharp & Dohme Corp. Composés dérivés de l'acide thiadiazolyl-oxyminoacétique
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